Cancers are composed of multiple cell types, including fibroblasts and epithelial cells; innate and adaptive immune cells; and cells forming blood and lymphatic vasculature; as well as specialized mesenchymal cell-types unique to each tissue microenvironment. While tissue homeostasis is maintained by collaborative interactions between these diverse cell types, cancer development is enhanced when genetically altered initiated cells harness these collaborative capabilities to favor their own survival and, in so doing, hijack or exploit normal physiological processes typically involved in maintaining tissue homeostasis. While previously supporting research programs focused solely on cancer and immunity, the expanded Cancer, Immunity, and the Microenvironment Program (Program) now supports research programs revealing insights into the interactions between evolving neoplastic cells with activated non-neoplastic host cells, and with soluble or insoluble components of extracellular matrix, as well as studies based on these interactions that foster development of novel cellular or molecular-based strategies to combat cancer. Specific scientific goals of the Program include: (1) to explore the relationship between neoplastic cells and stromal cells (i.e., immune, vascular, and mesenchymal) in mouse models of cancer to gain insights into the ability of stromal cells in the tumor microenvironment to promote or deter tumorigenesis; (2) to identify molecules and pathways in the tumor microenvironment that regulate anti-tumor activity; (3) to study the relationship between viral infections and malignancy, particularly in immunodeficient patients with HIV infection, and to develop new approaches for the prevention and treatment of malignancy in this population; and (4) to provide the basic scientific foundation and support for the application of new immune- or microenvironment-based therapeutics in cancer in conjunction with the organ-based Helen Diller Family Comprehensive Cancer Center (Center) Programs. With these expanded goals, the retooled Program grew to 27 faculty representing 13 departments in the School of Medicine. Faculty in the new Cancer, Immunity, and the Microenvironment Program are supported by $16,323,690 in NCI and other peer-reviewed grants per year, and published 612 scientific articles in the previous funding cycle. The Program has 6% intra-programmatic and 21% inter-programmatic publications.